PMID- 37192973 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20231028 IS - 2589-0042 (Electronic) IS - 2589-0042 (Linking) VI - 26 IP - 5 DP - 2023 May 19 TI - Natural gammadeltaT17 cell development and functional acquisition is governed by the mTORC2-c-Maf-controlled mitochondrial fission pathway. PG - 106630 LID - 10.1016/j.isci.2023.106630 [doi] LID - 106630 AB - Natural IL-17-producing gammadelta T cells (gammadeltaT17 cells) are unconventional innate-like T cells that undergo functional programming in the fetal thymus. However, the intrinsic metabolic mechanisms of gammadeltaT17 cell development remain undefined. Here, we demonstrate that mTORC2, not mTORC1, selectively controls the functional fate commitment of gammadeltaT17 cells through regulating transcription factor c-Maf expression. scRNA-seq data suggest that fetal and adult gammadeltaT17 cells predominately utilize mitochondrial metabolism. mTORC2 deficiency results in impaired Drp1-mediated mitochondrial fission and mitochondrial dysfunction characterized by mitochondrial membrane potential (DeltaPsim) loss, reduced oxidative phosphorylation (OXPHOS), and subsequent ATP depletion. Treatment with the Drp1 inhibitor Mdivi-1 alleviates imiquimod-induced skin inflammation. Reconstitution of intracellular ATP levels by ATP-encapsulated liposome completely rescues gammadeltaT17 defect caused by mTORC2 deficiency, revealing the fundamental role of metabolite ATP in gammadeltaT17 development. These results provide an in-depth insight into the intrinsic link between the mitochondrial OXPHOS pathway and gammadeltaT17 thymic programming and functional acquisition. CI - (c) 2023 The Author(s). FAU - Wang, Yunke AU - Wang Y AD - Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville, Louisville, KY, USA. AD - Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. AD - Department of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. FAU - Qin, Hui AU - Qin H AD - Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville, Louisville, KY, USA. AD - Department of Dermatology, Shanghai Jiaotong University Ruijin Hospital, Shanghai, China. FAU - Cai, Yihua AU - Cai Y AD - Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville, Louisville, KY, USA. FAU - Chen, Xu AU - Chen X AD - Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville, Louisville, KY, USA. AD - Department of Clinical Immunology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. FAU - Li, Hong AU - Li H AD - Functional Immunomics Core, Brown Cancer Center, University of Louisville, Louisville, KY, USA. FAU - Montoya-Durango, Diego Elias AU - Montoya-Durango DE AD - Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville, Louisville, KY, USA. FAU - Ding, Chuanlin AU - Ding C AD - Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville, Louisville, KY, USA. FAU - Hu, Xiaoling AU - Hu X AD - Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville, Louisville, KY, USA. FAU - Chariker, Julia H AU - Chariker JH AD - Department of Anatomical Sciences and Neurobiology, University of Louisville, Louisville, KY, USA. AD - Kentucky Biomedical Research Infrastructure Network Bioinformatics Core University of Louisville, Louisville, KY, USA. FAU - Sarojini, Harshini AU - Sarojini H AD - Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville, Louisville, KY, USA. FAU - Chien, Sufan AU - Chien S AD - Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville, Louisville, KY, USA. FAU - Rouchka, Eric C AU - Rouchka EC AD - Kentucky Biomedical Research Infrastructure Network Bioinformatics Core University of Louisville, Louisville, KY, USA. AD - Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY, USA. FAU - Zhang, Huang-Ge AU - Zhang HG AD - Department of Microbiology and Immunology, Brown Cancer Center, University of Louisville, Louisville, KY, USA. FAU - Zheng, Jie AU - Zheng J AD - Department of Dermatology, Shanghai Jiaotong University Ruijin Hospital, Shanghai, China. FAU - Qiu, Fuming AU - Qiu F AD - Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. AD - Department of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. FAU - Yan, Jun AU - Yan J AD - Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville, Louisville, KY, USA. LA - eng GR - R01 AI128818/AI/NIAID NIH HHS/United States PT - Journal Article DEP - 20230410 PL - United States TA - iScience JT - iScience JID - 101724038 PMC - PMC10182300 OTO - NOTNLM OT - Cell biology OT - Immunology OT - Molecular biology OT - Molecular mechanism of gene regulation COIS- Authors declare that they have no competing interests. EDAT- 2023/05/17 01:07 MHDA- 2023/05/17 01:08 PMCR- 2023/04/10 CRDT- 2023/05/16 21:16 PHST- 2022/07/20 00:00 [received] PHST- 2023/02/17 00:00 [revised] PHST- 2023/04/04 00:00 [accepted] PHST- 2023/05/17 01:08 [medline] PHST- 2023/05/17 01:07 [pubmed] PHST- 2023/05/16 21:16 [entrez] PHST- 2023/04/10 00:00 [pmc-release] AID - S2589-0042(23)00707-1 [pii] AID - 106630 [pii] AID - 10.1016/j.isci.2023.106630 [doi] PST - epublish SO - iScience. 2023 Apr 10;26(5):106630. doi: 10.1016/j.isci.2023.106630. eCollection 2023 May 19.